During pregnancy in sheep and in human beings plasma cortisol concentrations are increased without the compensatory decrease in plasma ACTH concentrations that would be expected with cortisol feedback inhibition of ACTH. Plasma ACTH concentrations are increased in pregnant sheep and in women plasma ACTH concentrations increase as pregnancy progresses. The responsiveness of the pituitary-adrenal axis to hypoglycemia is increased in pregnant ewes, whereas responses to hypotension and hypoglycemia appear to be decreased in ovariectomized ewes. This suggests either a chronic stimulatory effect of the sex steroids on ACTH secretion, a modulation of the responsiveness to stressors or an alteration in set-point of the axis. However, the ACTH response to hypotension is decreased during pregnancy, suggesting that the increase in responsiveness is not generalized. The sex steroids also appear to decrease AVP responses to hypotension during pregnancy, and this may alter the ACTH response to hypotensive stimuli or reflect the increase in blood volume or a change in baroreceptor responsiveness. the goal of this grant is to understand the alteration in control of plasma ACTH during pregnancy. The grant will focus on the role of the increase in estrogens and progesterone during pregnancy in increasing basal and stimulated ACTH and on the endocrine role of placental ACTH and CRF. The proposes studies will test for changes in episodic secretion of ACTH, in metabolism of ACTH and in the set-point for cortisol feedback control of the axis. Studies will also determine whether estrogen or progesterone increase ACTH responses to stress in pregnant ewes, and whether the effect of estrogen or progesterone occur centrally or peripherally, and is direct or indirect by altering blood volume or blood pressure. Studies will also determine if estrogen or progesterone alter AVP or CRF levels reaching the anterior pituitary or pituitary sensitivity to CRF or AVP. Although the placenta makes both ACTH and corticotropin- releasing factor (CRF), there is no significant tonic placental secretion into the circulation of either peptide in the pregnant ewe. Therefore, the role of ACTH and CRF in the placenta will be tested to determine if there is secretion during nonlabor or labor contractions. These studies are important to understanding the alteration in maternal responses to stress during pregnancy and to understanding the alteration in regulation of the pituitary-adrenal axis by sex steroids. Because maternal cortisol concentrations are the primary source of fetal cortisol for much of gestation, this understanding is important to our understanding of homeostasis in the fetus as well.